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PRIMARY PULMONARY HYPERTENSION WAQAS AHMED*, SABEEN RAZAQUE**, AYESHA KHALID*** familial form. The familial form is inherited as an autosomal dominant trait and is associated with a pattern of “genetic anticipation”; a worsening of disease in subsequent generations, manifested by greater severity or earlier onset6.

INTRODUCTION Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure without a demonstrable cause. Defined as a mean pulmonary artery pressure (PAP) >25mmHg at rest or >30mmHg during exercise1. PPH is also termed pre-capillary pulmonary hypertension or, more recently, idiopathic pulmonary arterial hypertension (IPAH). The diagnosis is usually made after excluding other etiologies that may cause secondary pulmonary hypertension (Table-1). Dresdale and colleagues first reported a hemodynamic account of PPH in 19512. Internationally, the incidence of primary pulmonary hypertension ranges from 1 to 2 cases per million people in the general population3. Prior to the 1990s, therapeutic options were limited. The recent emergence of prostacyclin analogues, endothelin receptor antagonists, and other novel drug therapies has greatly improved the outlook for patients with PPH and PPH-like diseases. PPH occurs at a femaleto-male ratio ranging from 2-9:1, depending on the treatment center sampled. No racial predilection is recognized. PPH typically develops in younger women of childbearing age. However, it can also affect women in their fifth and sixth decades of life or older. The mean age at presentation for PPH is fourth decade4.

Some cases may be related to sporadic genetic defects. The most common genetic defect in these cases is related to the BMPR-II gene. Mutations in transforming growth factor (TGF)-ß receptor 2, an important growth regulatory gene, have been described by Yeager and colleagues in endothelial cells in PPH. Such mutations have been proposed to impair the TGF-ß signaling system, an important growth suppressor, thus assisting in cell proliferation7,8. CLINICAL PRESENTATION: The average time from symptom onset to diagnosis has been reported to be approximately 2 years. In about 10 percent of patients, the diagnosis is not established until after three years of symptoms4. Early symptoms are nonspecific. Women are more likely to be symptomatic than men. The most common symptoms reported in a national prospective study by Rich, et al in 1987 were dyspnea (60%), weakness (19%) and recurrent syncope (13%)4. Physical findings in PAH can be quite variable. A loud P2 component of second heart sound which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction. Occasionally, the second heart sound may be palpable. Murmurs of tricuspid regurgitation & pulmonary regurgitation (Grahams Steell) are usually audible. A right ventricular heave may also be palpable. Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both. Large V waves are often present because of the commonly present severe tricuspid regurgitation.

FAMILIAL AND GENETIC VARIANT: A subset of the patients with PPH has a familial variant. Familial primary pulmonary hypertension accounted for 6 percent of the 187 cases in the NIH registry4. The histopathological and clinical features of the familial form of the disease are identical to those of the sporadic form,5 although, not unexpectedly, the diagnosis is made earlier in the *

Department of Cardiology, Shifa International Hospital, Islamabad correspondence. ** Department of Cardiology, Shifa International Hospital, Islamabad. *** Consultant Cardiologist, Shifa International Hospital, Islamabad.

Other findings may include hepatomegaly with palpable pulsations of the liver and an abnormal 51

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abdominal-jugular reflex. Ascites is not uncommonly present in untreated patients or in patients with worsening decompensated right heart failure. Pulmonary examination may be unremarkable. Variable degree of dependent edema may be present.

also been associated with pulmonary hypertension14,15. Whether these abnormalities are the cause or the result of the disease, however, remains uncertain.

PATHOPHYSIOLOGY:

ECG usually reveals right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. Some patients have few or no abnormal ECG findings; thus, normal ECG results do not exclude a diagnosis of PPH.

DIAGNOSTIC EVALUATION:

The pathophysiology of PPH is not well understood. But three elements combine to produce increased vascular resistance in patients with primary pulmonary hypertension: vasoconstriction, vascularwall remodeling, and thrombosis in situ. An insult (e.g., hormonal, mechanical etc.) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (the multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation. Early in the disease, as the pulmonary artery pressure increases, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. Thrombosis may result from injury to the endothelium, abnormal fibrinolysis, enhanced procoagulant activity, and platelet abnormalities9. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure10,11.

Chest radiography is usually the first diagnostic step in the evaluation of a patient with dyspnea; however, for many patients with PPH, the findings do not help reveal the underlying etiology of the pulmonary hypertension. Chest radiography is useful for excluding interstitial and alveolar processes that may cause hypoxia-mediated pulmonary vasoconstriction. Echocardiography is extremely useful for assessing right and left ventricular function, estimating pulmonary systolic arterial pressure, and excluding congenital anomalies and valvular disease. Pulmonary hemodynamics are markedly deranged, with increases in pulmonary-artery pressure to levels three or more times normal, elevated right heart pressure, and depressed cardiac output4. Pressures on the left side of the heart are usually normal, although extreme dilation of the right heart chambers can compress the left chambers to a degree that limits filling and produces small increases in diastolic pressures.

An imbalance between prostacyclin and thromboxane was first suggested by Christman et al, who found decreased urinary levels of 2, 3-dinor-6-ketoprostaglandin F1 , a metabolite of prostacyclin, as well as increased level of 11-dehydro-thromboxane B2, a thromboxane A2 metabolite, in patients with PPH as well as secondary pulmonary hypertension. Endothelial cells are the primary sites of prostacyclin synthase protein expression in the pulmonary circulation12. Tuder and colleagues reported decreased expression of prostacyclin synthase in small and medium-sized pulmonary arteries of patients with severe pulmonary hypertension13.

High-resolution chest CT scanning and ventilationperfusion lung scanning are frequently obtained to help exclude interstitial lung disease and thromboembolic disease. Pulmonary angiography may occasionally be required to help definitively exclude thromboembolic disease. While considered a high-risk procedure in patients with elevated pulmonary arterial pressures and/or right ventricular failure, a carefully performed study is generally safe21. Pulmonary function and cardiopulmonary exercise testing helps in the assessment of ventilatory efficiency and mechanical lung function can help differentiate intrinsic pulmonary vascular disease

Impaired synthesis of the endothelium-derived vasorelaxant nitric oxide and enhanced production of the endothelium-derived vasoconstrictor endothelin have 52

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PAKISTAN HEART JOURNAL drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. The use of these drugs produces a reduction in pulmonary vascular resistance by increasing the cardiac output and decreasing pulmonary artery pressure. It also improves the quality of life and survival rate, in patients who are proven "responders" to such therapy. A cardiac index of less than 2 L/min/m2 or elevated right atrial pressure above 15 mm Hg is evidence that CCBs may worsen right ventricular failure and, thus, may be potentially harmful to patients with PPH. In general, high doses of CCBs are used in patients with PPH; however, only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (e.g., with adenosine, epoprostenol, nitric oxide) derive any long-term benefit from CCBs (this corresponds to